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This single-center study will be conducted in 3 phases: a single-ascending dose phase (up to 8 cohorts, 8 subjects/cohort), a multiple-dose phase (up to 5 cohorts, 9 subjects/cohort), and a midazolam drug-drug interaction phase (one cohort of 8 subjects).
The single-dose phase initiates with ascending doses of an oral solution followed by a 3-way crossover food effect and bioavailability (capsule formulation) cohort. Serum IGF-1 levels and GHRH-analog stimulated GH levels will be assessed as pharmacodynamics measures.
The first multiple-dose (7 days dosing) cohort will be initiated after the PK and safety data are available from the single-dose phase. Subsequent multiple-dose cohorts will have 10 days of dosing. Serum IGF-1 level and GH levels will be assessed as pharmacodynamics measures.
The last cohort in the study is midazolam drug-drug interaction study. The dose will be selected based on review of all pharmacokinetic and safety data for the single-dose and multiple-dose cohorts completed. On Day 1, 8 subjects will receive a single oral 2 mg dose of midazolam. Starting on Day 3 through Day 8, subjects will receive daily doses of CRN00808. On Day 9, subjects will be administered CRN00808 and 2 mg midazolam together.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| CRN00808 Oral Solution | Experimental | CRN00808 oral solution, single-dose |
|
| CRN00808 Oral Capsule | Experimental | CRN00808 oral capsule, single-dose and multiple-doses |
|
| Placebo Oral Solution | Placebo Comparator | Placebo oral solution, single-dose |
|
| Placebo Oral Capsule | Placebo Comparator | Placebo oral capsule, single-dose and multiple doses |
|
| Midazolam Oral Solution | Other | Midazolam oral solution, two single-doses as part of the drug-drug interaction arm of the study |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| CRN00808 | Drug | Investigational drug |
|
| Measure | Description | Time Frame |
|---|---|---|
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] of CRN00808 single ascending doses using clinical assessments, telemetry, and Holter monitoring and subject self-reporting | ECG, clinical laboratory parameters, vital signs, physical examinations, telemetry, Holter monitoring | Day 1 through Day 10 |
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] of CRN00808 multiple ascending doses using clinical assessments and subject self-reporting | ECG, clinical laboratory parameters, vital signs, physical examinations | Day 1 through Day 21 |
| Measure | Description | Time Frame |
|---|---|---|
| AUC of CRN00808 single ascending doses | plasma AUC | Day 1 through Day 7 |
| Cmax of CRN00808 single ascending doses | plasma Cmax | Day 1 through Day 7 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jason Lickliter, MBBS PhD | Nucleus Network | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Nucleus Network | Melbourne | Victoria | Australia |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 35000098 | Derived | Madan A, Markison S, Betz SF, Krasner A, Luo R, Jochelson T, Lickliter J, Struthers RS. Paltusotine, a novel oral once-daily nonpeptide SST2 receptor agonist, suppresses GH and IGF-1 in healthy volunteers. Pituitary. 2022 Apr;25(2):328-339. doi: 10.1007/s11102-021-01201-z. Epub 2022 Jan 9. |
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| ID | Term |
|---|---|
| D008874 | Midazolam |
| ID | Term |
|---|---|
| D001569 | Benzodiazepines |
| D001552 | Benzazepines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
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Single and multiple-dose cohorts are placebo-controlled. The midazolam cohort does not have placebo.
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Double-blind study
| Placebo Oral Solution | Drug | Placebo |
|
| Midazolam oral solution | Drug | Midazolam as part of the drug-drug interaction arm of the study |
|
| Placebo oral capsule | Drug | Placebo |
|
| t1/2 of CRN00808 single ascending doses | plasma t1/2 | Day 1 through Day 7 |
| Tmax of CRN00808 single ascending doses | plasma Tmax | Day 1 through Day 7 |
| AUC of CRN00808 multiple ascending doses | plasma AUC | Day 1 through Day 20 |
| Cmax of CRN00808 multiple ascending doses | plasma Cmax | Day 1 through Day 20 |
| t1/2 of CRN00808 multiple ascending doses | plasma t1/2 | Day 1 through Day 20 |
| Tmax of CRN00808 multiple ascending doses | plasma Tmax | Day 1 through Day 20 |
| Pharmacodynamics of CRN00808 in single ascending dose cohorts assessed by GHRH analog stimulated GH levels | Suppression of serum GH induced by a GH secretagogue | Day -1 and Day 1 |
| Effect of CRN00808 on pharmacokinetics of midazolam | midazolam plasma AUC | Day 1 through Day 10 |
| Effect of CRN00808 on Cmax of midazolam | midazolam plasma Cmax | Day 1 through Day 10 |
| Effect of CRN00808 on t1/2 of midazolam | midazolam plasma t 1/2 | Day 1 through Day 10 |
| Effect of CRN00808 on Tmax of midazolam | midazolam plasma Tmax | Day 1 through Day 10 |
| Relative bioavailability of capsule formulation | single-dose crossover arm only | Day 1 to Day 7 |
| Effect of food on Cmax of CRN00808 | plasma Cmax compared with and without food in single dose arm | Day 1 to Day 7 |
| Effect of food on AUC of CRN00808 | Plasma AUC compared with and without food in single dose arm | Day 1 to Day 7 |
| Pharmacodynamics of CRN00808 in multiple ascending dose cohorts assessed by serum IGF-1 and GH | serum IGF-1 and GH | Day -1 to Day 21 |
| D006571 | Heterocyclic Compounds |